Electrical impedance techniques in tissue-mass detection and characterization

ABSTRACT

A device is described for measuring electrical characteristics of biological tissues with plurality of electrodes and a processor controlling the stimulation and measurement in order to detect the presence of abnormal tissue masses in organs. Examples of suitable organs are the breast, skin, oral cavity, lung, liver, colon, rectum, cervix, and prostate and determine probability of tumors containing malignant cancer cells being present in tissue. The approach can also be applied to biopsied tissue samples. The device has the capability of providing the location of the abnormality. The method for measuring electrical characteristics includes placing electrodes and applying a voltage waveform in conjunction with a current detector. A mathematical analysis method is then applied to the collected data, which computes spectrum of frequencies and correlates magnitudes and phases with given algebraic conditions to determine mass presence and type.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application claims priority as a continuation-in-part ofU.S. patent application Ser. No. 13/300,600 filed Nov. 20, 2011 entitled“USE OF IMPEDANCE TECHNIQUES IN BREAST-MASS DETECTION,” that is acontinuation-in-part of U.S. patent application Ser. No. 12/874,192filed Sep. 1, 2010 entitled “USE OF IMPEDANCE TECHNIQUES IN BREAST-MASSDETECTION,” and also claims priority to U.S. provisional applicationSer. No. 61/238,949 filed on Sep. 1, 2009 entitled “USE OF IMPEDANCETECHNIQUES IN BREAST-MASS DETECTION.” The disclosures of each of thesepatent applications are herein incorporated by reference in theirentirety.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference in their entirety to the sameextent as if each individual publication or patent application wasspecifically and individually cited to be incorporated by reference.

REFERENCES

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[2] Tyna A Hope and Sian E Iles, The use of electrical impedancescanning in the detection of breast cancer. Breast Cancer Res. 2004;6(2): 69-74.

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[4] Arum Han, Lily Yang and A. Bruno Frazier, Quantification of theHeterogeneity in Breast Cancer Cell Lines Using Whole-Cell ImpedanceSpectroscopy, Clinical Cancer Research 13, 139, Jan. 1, 2007. doi:10.1158/1078-0432.CCR-06-1346.

-   [5] Alexander Stojadinovic, Aviram Nissan, Zahava Gallimidi, Sarah    Lenington, Wende Logan, Margarita Zuley, Arieh Yeshaya, Mordechai    Shimonov, Moshe Melloul, Scott Fields, Tanir Allweis, Ron Ginor,    David Gur, and Craig D. Shriver, Electrical Impedance Scanning for    the Early Detection of Breast Cancer in Young Women: Preliminary    Results of a Multicenter Prospective Clinical Trial, Journal of    Clinical Oncology, Volume 23, Number 12, Apr. 20, 2005: 2703-2715.-   [6] WANG Kan, WANG Ting, FU Feng, JI Zhen-yu, LIU Rui-gang, LIAO    Qi-mei and DONG Xiu-zhen, Electrical impedance scanning in breast    tumor imaging: correlation with the growth pattern of lesion,    Chinese Medial Journal 2009; 122(13):1501-1506.-   [7] T. Morimotoa, Y. Kinouchib, T. Iritanic, S. Kimura Y.    Konishia, N. Mitsuyamaa, K. Komakia, Y. Mondena, Measurement of the    Electrical Bio-Impedance of Breast Tumors, European Surgical    Research Vol. 22, No 2, 1990; 22:86-92 (DOI: 10.1159/000129087).-   [8] Alexander Stojadinovic, M.D., Aviram Nissan, M.D., Craig D.    Shriver M.D., Sarah Lenington, Ph.D., David Gur, Sc.D, Electrical    Impedance Scanning for Breast Cancer Risk Stratification in Young    Women, Hermann Scharfetter, Robert Merva (Eds.): ICEBI 2007, IFMBE    Proceedings 17, pp. 675-678, 2007.-   [9] Mohr, P. Ulrik Birgersson, P. U., Berking, C., Henderson, C.,    Trefzer, U., Kemeny, L., Cord Sunderkotter, C., Dirschka, T.,    Motley, R., Frohm-Nilsson, M, Reinhold, U., Loquai, C., Braun, R.,    Nyberg, F., and J. Paoli, Electrical impedance spectroscopy as a    potential adjunct diagnostic tool for cutaneous melanoma, Skin    Research and Technology 2013; 19:75-83 (doi: 10.1111/srt.12008).-   [10] Yung, R. C., Zeng, M. Y., Stoddard, G. J., Garff, M, and K.    Callahan, Transcutaneous Computed Bioconductance Measurement in Lung    Cancer, Journal of Thoracic Oncology, Vol 7, Number 4, pp. 681-689,    April, 2012.-   [11] Laufer, S., Ivorra, A., Reuter, V. E., Rubinsky, B., and S. B.,    Solomon, Electrical impedance characterization of normal and    cancerous human hepatic tissue, Physiol Meas. 2010 July;    31(7):995-1009. doi: 10.1088/0967-3334/31/7/009. Epub 2010 Jun. 24.-   [12] Gupta, D., Lammersfeld, Carolyn A., Burrows, Jessica L., Dahlk,    Sadie L., Vashi, P. G., Grutsch, J. F. Hoffman, Sra, and C. G. Lis,    Bioelectrical impedance phase angle in clinical practice:    implications in advanced colorectal cancer, Am. J. Clin. Nutr,    80:1634-8, 2004.-   [13] Tidy, J. A., Brown, B. H., Healey, T. J., Daayana, S., Martin,    M, Prendiville, W. and H C. Kitchenerg, Accuracy of detection of    high-grade cervical intraepithelial neoplasia using electrical    impedance spectroscopy with colposcopy, DOI:    10.1111/1471-0528.12096.-   [14] Wan, Y., Borsic, A., Heaney, J., Seigne, J., Schned, A., Baker,    M., Wason, S., Hartov, A, and R. Halter, Transrectal Electrical    Impedance Tomography of the Prostate: Spatially Co-registered    Pathological Findings for Prostate Cancer Detection, Med Phys    40:063102. 2013.

FIELD OF THE INVENTION

The application of a signal to tissue and differentiating tissuecharacteristics such as the presence of benign or malignant growths fromnormal tissue based on impedance characteristics.

BACKGROUND OF THE INVENTION

Bio-impedance of breast tumors has been a source for numerous scientificresearch studies since discovery of electricity by Volta in 1800. It wasthe Cole brothers (in 1930) who mathematically and physically describeddielectric properties. Cole-Cole equations are used in bio-impedanceanalysis. Since the late 1960's, bio-impedance analysis has benefitedfrom the advent of microprocessors and digital signal processing.

The method can also be used to characterize biological tissue electricalproperties in many different applications including blood analysis, bodymuscle and fat content as well as in estimating the length of the rootcanal in teeth see U.S. Pat. No. 6,425,875 “Method and device fordetection of tooth root apex.”

Electrical Impedance Scanning (EIS) has been described in literature [1][2] and machines have been built to be used on patients. The EIS of thebreast relies on body transmission of alternating electricity using anelectrical patch attached to the arm and a hand-held cylinder. Theelectrical signal flows through the breast where it is then measured atskin level by a probe placed on the breast. Examples of such devices arethe T Scan 2000 from Mirabel Medical Systems, which has been cleared bythe FDA for adjunctive diagnosis in conjunction with mammography, andthe follow-on T Scan 2000 ED. Mirabel devices are covered under multiplepatents among which are Andrew L. Pearlman (U.S. Pat. No. 7,141,019),Ron Ginor (U.S. Pat. No. 7,302,292) and Ginor and Nachaliel (U.S. PatentApplication Pub. No. 2007/0293783). Other devices are the one fromBiofield Corp. (Cuzick et al, U.S. Pat. No. 6,351,666), and the deviceof Richard J. Davies (U.S. Pat. Nos. 6,922,586 and 7,630,759).

The benefits of having a non-mammographic mechanism to screen forpatients whose age is less that age 50 are significant. Below age of 40,radiation from use of screening mammography will cause more cancer thanit saves. Between 40 and 50 there is a break even where one savesapproximately as many of cancers caused. Above 50 years of agemammography works well because a tumor contrasts well against normalbreast tissue. After age 50, fat content increases; since fat is darker,there is a contrast of normal breast tissue to cancer tissue. Below age40 the density of the breast tissue is so high that it is difficult toimpossible to differentiate from a tumor. The same is not quite as truefor women in the age group of 40 to 50 but the problem with mammographicdifferentiation between normal breast tissue and cancer remains.

Asymptomatic young women under the age of 40 are not routinely screened(in the United States) but instead depending on breast self-examination(BSE) and clinical-breast examination (CBE). Carcinoma of the breast isgenerally more aggressive in younger women. The availability of adiagnostic test that does not involve radiation would be of significantbenefit.

Mammograms only demonstrate presence of calcium and not all DCIS masseshave calcium deposits. MRI and PET only detect increases in vascularitythat may or may not be present. One consideration in mammography is thatthe results are not necessarily stable; some 30% of “cancer” detected onmammography disappears.

Another factor is the detection of breast cancer, and otherabnormalities, is the cost of doing procedures. It would of significantbenefit, particularly in developing countries, to have a low costprocedure. Of course, lower cost and resulting wider availability isimportant in developed nations as well.

SUMMARY OF THE INVENTION

Breasts can be examined using an electrical impedance scanning method,which has been previously described in many publications [1] [2] [3]. Inthis novel invention, the method is improved to quickly scan throughmultiple frequencies by using a complex waveform containing even and oddharmonics across several decades of frequencies.

Uses are:

-   -   1. Detection of Ductal Carcinoma In Situ (DCIS) other malignant        tumor masses, or benign breast masses    -   2. Follow up of changes in masses over time    -   3. Assess effectiveness of treatment to eradicate DCIS or other        tumors.

The invention provides significant benefits, first by avoiding use ofradiation which can generate the cancers that mammography that the testis meant to detect and perhaps other cancers and second by offering alow-cost diagnostic test and tracking vehicle.

Impedance systems and methods can be applied to tissues from any part ofthe body to search for the detection of, location of, andcharacterization tissue abnormalities including differentiation betweenbenign and malignant masses. Mohr et al. [9] addressed melanoma (using35 different frequencies, logarithmically distributed from 1.0 kHz to2.5 MHz), Yung et al. addressed the lung [10], Lauder et al. [11] theliver (in the frequency range of 1 to 400 kHz), Gupta et al. [12] thecolon, Tidy et al. [13] the cervix (frequency ranging from 76.3 to 625kHz in 14 steps), and Wan et al. [14] (frequencies of 0.4 kHz, 3.2 kHzand 25.6 kHz). All of the preceding do not use stimulation withsimultaneous multiple frequencies and use standard impedance techniquesrather than the ratio-metric approach that is the novelty of the currentinvention. This invention can be used in humans or animals.

The invention provides significant benefits, first by avoiding use ofradiation which can generate the cancers that mammography that the testis meant to detect and characterize other cancers and second by offeringa low-cost diagnostic test and tracking vehicle.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a block diagram of the impedance application system.

FIG. 2 illustrates the source waveform with all even and odd harmonics.

FIG. 3 shows the phase of the source waveform.

FIG. 4 illustrates the magnitude response of regular breast tissue.

FIG. 5 shows the phase response of a regular breast tissue.

FIG. 6 illustrates the magnitude response of tumor tissue.

FIG. 7 shows the phase response of a regular and tumor tissue.

FIG. 8 shows saw tooth waveform.

FIG. 9 shows the FFT magnitude of the saw tooth waveform.

FIG. 10 shows the FFT phase of the saw tooth waveform.

FIG. 11 illustrates the breast-impedance configuration with amultiple-electrode source.

FIG. 12 illustrates the breast-impedance configuration with asingle-electrode source.

FIG. 13 illustrates the breast-impedance configuration with asingle-electrode source and illustrating a breast mass.

FIG. 14 illustrates the breast-impedance configuration with asingle-electrode source showing the movement trajectory of thatelectrode to allow three-dimensional reconstruction.

FIGS. 15A and 15B illustrate the test configuration for melanoma.

FIG. 16 illustrates the test configuration for the oral cavity.

FIG. 17A and 17B illustrate the test configuration for the lung.

FIG. 18 illustrates the test configuration for the liver.

FIG. 19 illustrates the test configuration for the colon or rectum.

FIG. 20 illustrates the test configuration for the cervix.

FIGS. 21A and 21B illustrate alternative test configurations for theprostate.

FIG. 22 illustrates the test configuration for tissue biopsy specimens.

DETAILED DESCRIPTION OF THE INVENTION

The amplitude and phase of several harmonics within a range offrequencies creates a signature of the breast growths allowingdifferentiation of benign and malignant masses. Our invention is novelin that it differentiates normal from abnormal tissue based on observingsecondary effects of changes in dielectric properties due to increasednumbers of cells based on phase and amplitude of multiple levels ofharmonics without the necessity to measure absolute capacitance andresistance values. The invention allows differentiation of benign masses(e.g., tumor or infections) versus malignant masses versus othercellular changes. Our approach is not impacted by patient-to-patientdifferences.

Other impedance-related approaches (e.g., those referenced above fromMirabel Medical Systems, Biofield, and Davies) depend on measuringabsolute capacitive and absolute resistive properties to compute theCole-Cole function shape. Measuring absolute values is difficult andinherently error prone, especially since they will vary from patient topatient.

To analyze measurements by searching for simultaneous interactionsbetween multiple frequencies, the obvious choice is to use Fast FourierTransform or Discrete Fourier Transform. However there other transformsthat may give very specific and different advantages.

Chirp-Z Transform has an advantage of having the ability to focusanalysis on specific band of frequencies by performing spectra zooming.The range of data points does not have to be equal to 2^(n) and in itszoomed form it can be continuously moved to mark time information of theanalyzed data.

-   Chirp-Z Transform:

${{CZT}\left( {x\lbrack n\rbrack} \right)} = {\sum\limits_{n = 0}^{N - 1}{{x\lbrack n\rbrack} \cdot z_{k}^{- n}}}$Wavelet Transform or Discrete Wavelet Transform has an ability toresolve time and frequencies within the uncertainty principle.

-   Wavelet Transform is two-dimensional:

${{CWT}_{x}^{\Psi}\left( {\tau,s} \right)} = {\frac{1}{\sqrt{s}}{\int{{{x(t)} \cdot \Psi}*\left( \frac{t - \tau}{s} \right){\mathbb{d}t}}}}$Uncertainty principle:

${{\Delta\; t\;\Delta\; f} \geq \frac{1}{4\;\pi}}\;$FFT/DFT transforms show interactions between frequencies and the sameinteractions will be shown when using Chirp-Z or Wavelet transform.

The additional information these last two transforms bring, whiletesting tissue, could be used to further mark the signature of thesecells for differentiation.

An embodiment of a suitable device is shown in the Block Diagram of FIG.1, which illustrates the block diagram of the invention for breast-massdetection. After the unit powers up through the use of user interface100, the microprocessor 110 will load the characteristics of the desiredsquare wave to the generator 120. If another wave type were used (e.g.,sine or saw tooth), generator 120 would generate that wave type. Ascommanded by the medical professional through the input interface 100,the microprocessor 110 will start coherent sampling by synchronizing thewaveform generation 120 and waveform capture 150. Output stage 130assures proper voltage levels and their rising and falling edges. Theoutput stage 130 also distributes the signal to multiple electrodes asshown in FIG. 11. Microprocessor 110 controls the main frequency andtriggers the current capture 150. The biological tissue 140 is thebreast under examination. The sampled current 150 is digitized by Analogto Digital Converter (ADC) 160. A Fast Fourier Transform (FFT) iscomputed by microprocessor 110 on 2^(n) samples received from ADC 160.For practical considerations, the n should be equal or greater than 8.Typically it would be 12, but with microprocessor advances this can beincreased for better accuracy. The resulting FFT data with its magnitudeand phase are compared by the microprocessor 110 with the identifyingreferences stored in it. The references may include markers identifyingbenign or malignant tumors including their relative position to a probesbeing tested. All the conclusions of testing by the microprocessor 110are sent to the display 100 to inform the medical professional. Thecircuit requires coherent source and sampling conditions to achieve thespectral resolution needed to precisely identify changes in amplitudesand phases caused by masses, including growing cancer cells. Coherentsampling is superior over any type of data windowing or interpolation. Awide spectral band is used from around 20 kHz to several MHz with oddharmonics. The non-linearities in the tissue will contribute togeneration of even harmonics at much smaller amplitude. Our inventioncan be used in the ranges of 10 kHz to 1 MHz, or from 1 MHz toapproximately 100 MHz, and from 100 MHz to 10 GHz.

In one embodiment, the square wave main frequency 200 in FIG. 2 is setto 10.74219 kHz. This satisfies the coherency condition of 11 cycles,4096 samples and 250 ns sampling. It places the 93^(rd) 210 harmonic at999.0234 kHz. This setting takes into computation 48 harmonics. Researchpapers have indicated 100 kHz to 1 MHz to be affected by growing tumorcells [4] [5]. The square wave rising and falling edges were set to 250ns giving odd harmonic content.

All harmonics in the band of the source square wave, as shown with theirmagnitude in FIG. 2 and the phase in FIG. 3, are used in thecomputation. The results of magnitude and phase changes 300 in FIG. 3are compared with the set of the reference amplitudes and phases as theyidentify cancer cells [2] [6] [7] [8]. Alternatively, a set of referenceamplitudes and phases as they identify masses of benign cells can beused.

FIG. 4 shows an example of breast-tissue current with its magnituderesponse to the square-wave stimulus and FIG. 5 with its phase response.The model of a tumor tissue includes a non-linear capacitor. Theharmonic level 400 in FIG. 4 is shifted to larger value. The phase plot500 in FIG. 5 has changed shape. FIGS. 6 and 7 respectively showexamples of breast-tissue current in magnitude 600 in FIG. 6 and phaseresponses to the square-wave stimulus for malignant breast tissue. FIG.7 compares healthy tissue response with tumor tissue response 700.

The phase and amplitude changes across multiple frequenciesdifferentiate the tissue into healthy cells, benign mass, and malignanttumor. The amount of phase shift at particular frequencies creates amarker to be identified during clinical studies. Having in excess of 40harmonics, the cell signature makes the differentiation very visible.

Some of the scientific publications show analysis of dielectricproperties of tumor cell in the frequency range up to 10 GHz. A modifiedsaw tooth waveform 800 in FIG. 8 with coherent ratio between its period810 and sampling interval would cover this range. The plateau 820 in thesaw tooth could be made variable to tune in into the response ofspecific tumor cells.

The magnitude of Fast Fourier Transform is shown on FIG. 9. The waveformshows both even and odd harmonics 900. The phase response of the sawtooth waveform shown in FIG. 10 exhibits small variations in thebandwidth of interest 1000.

The waveform sources 1100 are distributed around the breast 1150 atconstant separation angles as shown in FIG. 11. The nipple is used toconnect the detector 1110. The connection can be made via a cap or othersurface connection or via an inserted probe. Generating waveforms andcollecting data are done by stand-alone device 1120. The resulting dataare transferred to a computer 1130 for visual and mathematical analysis.The receiving electrode 1110 in FIG. 11 may be one covering the nipple,or for increased localization capability may be an electrode made ofinsulated wire with a bare conducting tip inserted into one of the(typically on the order of nine) milk ducts. The localization is inthree dimensions. For differentiated signatures, this approaches permitsgreater localization. In another embodiment the source and receivingelectrodes are incorporated in a brassiere. This electrode configurationcan be effectively employed for screening where a mass is not palpableor the situation where a mass is palpable.

The ECG/EKG pads are distributed in the area where breast attaches tothe chest wall. The ECG/EKG pads can be replaced with 30 gauge needlesto achieve a higher degree of accuracy.

The system is not limited to the use of a square wave. A sine wave canbe used with the same coherent setting for multiple frequencies coveringsimilar or the same harmonics. There could be one sine wave source witha non-linear gain element creating harmonics without need to step thefrequencies.

Analyzing magnitude and phase for over 40 harmonics in frequency spanfrom 10 kHz to 1 MHz will be a substantial source for the signaturedifferentiating dielectric properties of healthy tissues versus tumortissue. Many publications show Cole-Cole charts with significant changeswhen tumor cell start to grow in this frequency span.

In other embodiments, the number of source electrodes is varied. Thelarger the number of source electrodes, the higher the resolution oflocalization. For example having eight source electrodes arranged aroundthe perimeter of the breast will double the localization capabilitysince the area of the breast will be divided into eight regions asopposed to quadrants. Where in some applications of the device, one onlywants to do screening to know whether a lesion is likely present or not,in others being able to localize would be important. This may occur, forexample, if one is tracking changes in the lesion. Tracking can be doneby taking a base measurement, instilling a therapeutic agent in one or aplurality of milk ducts, and assessing the progress of treatment viafollow-up measurements.

An alternative source electrode configuration is shown in FIG. 12 forbreast 1250. This has a single source probe electrode 1205 withreceiving electrode 1210. Generating waveforms and collecting data isdone by stand-alone device 1220. The resulting data is transferred to acomputer 1230 for visual and mathematical analysis. The configuration ofFIG. 13 shows the configuration of FIG. 12 in conjunction with breast1350 containing an example lump 1315 characterized by employing sourceelectrode (probe) 1305 and receiving electrode 1310. Generatingwaveforms and collecting data are done by stand-alone device 1320. Theresulting data are transferred to a computer 1330 for visual andmathematical analysis. In this configuration, three-dimensionalreconstruction is not required because the impedance characteristicswould be determined for a single palpable mass over which the electrodeis placed. In this mode, the device is used for evaluation of a givenmass as opposed to screening for a non-palpable breast mass.

FIG. 14 demonstrates a variation of configurations of FIGS. 12 and 13 inconjunction with breast 1450 in which source probe electrode 1405 ismoved around the base of the breast 1450 with the single receivingelectrode 1410. Generating waveforms and collecting data are done bystand-alone device 1420. The resulting data are transferred to acomputer 1430 for visual and mathematical analysis. In thisconfiguration, movement of the single-source probe electrode 1405 aroundthe base of breast 1450 in a roughly circular trajectory allows datacollection of the type in FIG. 11 in which a three-dimensionalreconstruction and thus 3-D localization of a breast mass can beaccomplished. The position of the single-source probe and its movementcan be shown on the computer screen so the program knows for whichlocation data is collected. Thus this configuration can be used forscreening in which a breast mass can be detected and characterizedthrough its signature, whether than mass was palpable or not.

Feedback to the user as to results may take multiple forms. In oneembodiment, the presence an abnormality is a non-visual feedback. Thisis supplied by an auditory or vibratory cue. Tone patterns can provideeither a binary or relative magnitude, including level of probability.In another embodiment, the presence of an abnormality is indicated by asimple visual cue such as an LED display, either binary or relativemagnitude, including level of probability.

In another embodiment, the presence of an abnormality is indicated by anintermediate visual display presenting text or graphical results,including level of probability and 3-D location. In still anotherembodiment, the presence of an abnormality is indicate by a complexvisual display presenting raw data and processed graphical information,including level of probability.

The invention can be used as a screening device for initial,non-radiation involving, low-cost exam where, if the result is positive,a higher functionality version of the invention is used (for example,one with full display capabilities) and/or other techniques such asmammography, Magnetic Resonance Imaging, Positron Emission Tomography,and ultrasound. For screening purposes it is usually important to adjustthe detection level so that the results are biased to having falsepositives and avoiding false negatives since the false positive testscan be followed up more intensively, or, in some cases, by repetition ofthe initial type of test. One can adjust relationships among truepositives and negatives and false positives and negatives. Specificityand sensitivity can be adjusted as well.

An important approach to the testing of such devices is the ability ofcomparing the healthy tissue in one breast to a potential lesion in theother breast in the same patient.

FIGS. 15 A and B show the test configurations for melanoma. FIG. 15Aillustrates the test instrument applied to potential melanomas on theface with spring-action electrodes 1500 being applied with only the tipsconductive and handle with wires 1510. FIG. 15B shows the electrode pairused to confine skin lesions as illustrated in FIG. 15A. Spring-actionelectrodes 1530 have exposed semicircular electrodes 1550 at the tips(one of which is the source electrode and the other the receivingelectrode and which one is which is arbitrary). Spring-action electrodes1530 are covered by insulation 1540 and are connected to the electronicinstrumentation by wires 1560 and become embedded in cable 1570. In oneembodiment, the semicircular electrodes are between 7 to 12 millimetersin diameter and separated up to 15 mm. The electrodes are insulated sothey can touch each other if pushed together without shorting.

FIG. 16 shows the oral cavity with such structures as the upper lip1600, lower lip 1620, tongue 1610, tonsil 1630, and uvula 1640. The oralcavity is accessible and lesions often superficial. Theimpedance-measurement interface consists of a tweezers-style electrodepair 1650 insulated to the electrode active areas 1660 with source andreceiving electrodes (which one is which does not matter) connected tocable 1670. The impedance-measurement interface can be applied any ofthe mentioned structures but any other included structures such as themucosa of the cheeks, the gingiva, or the oral pharynx. If an area suchas the tongue is sensitive, the area being measured can first have ananesthetic topically applied.

FIG. 17 shows the testing configuration for the lung. Measurements canbe made on the anterior of the patient as shown in FIG. 17A or theposterior surface as shown in FIG. 17B. In FIG. 17A, source electrode1700 can be preferentially located above the shoulder just posterior toclavicle or at position 1710 on the lateral surface of the side of thethorax being examined, in this case the left side of the patient. Thereceiving electrodes 1730 are located laterally to sternum 1720 locatedin the midline. Any if the electrodes are to be placed in theintercostal spaces or other areas (e.g., posterior to the clavicle) tominimize the interference of underlying cartilage or bone. FIG. 17Bcovers impedance measurements on the posterior surface of the patient.In FIG. 17B, source electrode 1750 can be preferentially located abovethe shoulder just posterior to clavicle or at position 1760 on thelateral surface of the side of the thorax being examined, in this casethe left side of the patient. The receiving electrodes 1780 are locatedlaterally to spine 1770 located in the midline

FIG. 18 shows the test configuration for the liver. In FIG. 18, liver1800 is contained within rib cage 1810 anchored by sternum 1820 withsource electrode 1840 placed laterally on the side of the patient (orwith alternative position at the position of the receiving electrode1850), typically also posteriorly, with receiving electrodes (suggestedto be) the source electrode 1850 (open-square symbols) placed over thesurface of the skin overlying liver 1800. As was true for the lungabove, the source and receiving electrodes are placed in the intercostalspaces or below the rib cage if the liver protrudes inferiorly to therib cage to avoid interference by cartilage or bone.

FIG. 19 shows the test configuration for the colon or rectum. Insideabdomen, 1900 is rectum 1910 and colon 1920. Specially outfittedcolonoscope 1930 is threaded through the anus through rectum 1910 andthe body of colon 1930 to the lesion of be assessed at location 1940 atwhich a semicircular electrode configuration of the type shown in FIG.15B with one of the semicircular electrodes being the source electrodeand the other the receiving electrode. The semicircular electrodes canbe applied to lesions within the rectum as well as those within thecolon.

FIG. 20 shows the test configuration for the cervix in the context of across section of the pelvis. The organs shown are the vagina 2000, theuterus 2010, rectum 2020, bladder 2030, and cervix 2040. To analyzecervix 2040, instrumented speculum 2050 is introduced through vagina2000 and semicircular electrodes 2060 are applied to lesions on cervix2040 with the electrodes connected to the impedance analyzer throughwires 2070. The same instrumentation can be applied to masses in thevaginal cavity other than the cervix. The vaginal cavity is accessibleand lesions often superficial.

FIG. 21 shows test configurations for the prostate with FIG. 21A andFIG. 21B illustrating alternative electrode configurations. Organs shownin the vertical section of FIG. 21A are rectum 2100, bladder 2105,testis 2110, penis 2115, urethra 2120, and prostate gland 2125. Thesource electrode 2130 provides one side of the impedance analysiscircuitry and receiving electrode 2135. Alternatively, the receivingelectrode could be located at a different position 2140. Sourceelectrode 2130 and one or both of receiving electrodes 2135 and 2140 areconnected with the impedance analysis instrument (not shown) by wires2145. FIG. 21B shows a vertical section through the male pelvic regiondemonstrating an alternative mechanism for doing the impedancemeasurement and analysis. The organs illustrated are the rectum 2160,prostate 2165, testis 2170, penis 2175, and urethra 2180. In thisembodiment, the source electrode 2185 is placed in urethra 2180 and thereceiving electrode 2190 are both connected to the impedance analysisinstrument (not shown) by wires 2195.

FIG. 22 shows the test configuration for performing impedance analysesof biopsied tissue samples. The source electrode is a plate 2200 onwhich the tissue sample is placed and is connected to the impedanceanalysis instrument (not shown) by wire 2210. Plate 2200 is onlyconductive on the top surface; the sides and bottom are insulated. Thetissue sample has its bottom resting on source electrode plate 1900 andthe top of the sample has a receiving electrode 2220, typically a disk 7to 15 mm in diameter pressed into it. Receiving electrode 2220 issecured to insulated handle 2230. Wire 2240 connects receiving electrode2220 to the impedance analysis instrument (not shown). The surfaces ofthe plate 2200 or receiving electrode 2220 may be flat, curved, or anarbitrary shape.

While the approach described is applied to breast tissue, the sametechniques with the same parameters can be applied for detectingabnormalities in other tissues, including, but not limited to, forexample, lung and prostate tissue, using suitable source and receivingelectrodes.

It is noted that any embodiment described herein for exemplary purposesis, of course, subject to variations. Because variations and differentembodiments may be made within the scope of the inventive concept(s)herein taught, it is to be understood that the details herein are to beinterpreted as illustrative and not in a limiting sense.

The invention claimed is:
 1. A method for testing presence,characterization, and tracking of benign or malignant masses the methodcomprising: a. applying a wide range coherent frequency stimulationsource signal with voltage receiving electrodes attached one of morefirst locations on or in the patient, b. measuring a wide-band currenttissue response signal to the applied source signal with a currentsource electrode placed at one or more second locations on or in thepatient; c. with a computer program stored on a non-transient computermedium executed by a processor, performing the steps of: a. correlatingthe measured tissue response signal with the applied source signal; b.calculating a transform selected from the group consisting of FastFourier Transform, Discrete Fourier Transform, Chirp-Z Transform,Wavelet Transform and Discrete Wavelet Transform of the correlatedsource signal and tissue response signal to determine a ratio-metricmeasurement; c. comparing the determined ratio-metric measurement withderived ratios created in clinical studies indicative of healthy, benignand malignant tissue; d. classifying the determined ratio-metricmeasurement as one of healthy, benign, and malignant tissue based on thecomparison of the determined ratio with the derived ratios; e. locatinga mass, if present, based on the origin of the tissue response signal;and indicating the results to the user.
 2. The method of claim 1 whereinthe wide range frequency stimulation is used from with even and oddharmonics is selected from the group consisting of 20 kHz to 1 MHz, 1MHz to 100 MHz, and 100 MHz to 10 GHz coherently sampled between theoutput stage and wide-band current measurement input.
 3. The method ofclaim 1 wherein the excitation waveform of the applied stimulationsource signal is selected from the group consisting of square wave, sinewave, and triangle wave.
 4. The method in claim 1 wherein the indicatingthe results to the user comprises: indication of the presence of anabnormality selected from the group consisting of auditory cue,vibratory cue, simple visual cue of either binary or relative magnitude,including level of probability, intermediate visual display presentingtext or graphical results, including level of probability, and complexvisual cue display presenting raw data and processed graphicalinformation, including level of probability.
 5. The method in claim 1used in screening where if a result is positive, confirmation is soughtby use of a technique selected from the group consisting of mammography,Magnetic Resonance Imaging, Positron Emission Tomography, ultrasound,and tissue histology.
 6. The method in claim 1 where adjustments aremade in parameters selected from the group consisting of specificity,sensitivity, true positives, false positives, true negatives, and falsenegatives.
 7. The method in claim 1 applied to breast masses in which a.one or a plurality of source electrodes attached where a breast joinsthe chest wall of a patient, b. a receiving electrode attached to thenipple of the same patient.
 8. The method in claim 1 applied to prostatemasses in which c. one or a plurality of receiving electrodes areattached to the perineal skin in close proximity to the underlyingprostate of the patient, and d. a source electrode is placed in theurethra at the level of the patient's prostate.
 9. The method in claim 1applied to masses in directly accessible superficial organs selectedfrom the group consisting of skin, oral cavity, vaginal cavity, rectum,and colon in which a. the receiving electrode is a semicircle that isone half of a circular electrode pair applied to surround a patientlesion, and b. a source electrode is a semicircle that is the other halfof the circular applied to surround the patient lesion.
 10. The methodin claim 1 applied to lung masses in which a. one or a plurality ofreceiving electrodes are attached to the parasternal skin in theintercostal spaces on the side of the thorax being analyzed withcomplementary positions on the back of the patient, and b. the sourceelectrode at the one or more positions on the side to be analyzedselected from the group consisting of lateral thorax and the top of thethorax posterior to the clavicle.
 11. The method in claim 1 applied toliver masses in which a. one or a plurality of receiving electrodesattached to the skin over the liver in the intercostal spaces, and b. asource electrode at a position selected from the group consisting of inan intercostal space on the lateral right and just under the lower partof the sternum.
 12. The method in claim 1 for testing of benign ormalignant tissue biopsy specimens, the method comprising: a. one or aplurality of receiving electrodes on one face of a tissue biopsyspecimen, and b. a source electrode located on the opposite face of thetissue biopsy specimen.